Furo-(3,4-C)-pyridine derivatives and therapeutic compositions containing the same

ABSTRACT

This invention relates to 1,3-dihydro-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine derivatives of the general formula I ##STR1## wherein each of A 1  and A 2  independently represents various hydrocarbon groups and therapeutically acceptable addition salts thereof; to a process for the preparation of the same comprising oxidizing the secondary alchol α 4 , 3-o-isopropylidene-1-methyl-5-(1-hydroxy-1-A 1 )-methyl pyridine by any usual technique, reacting the resultant ketone with a compound of the general formula XA 2  wherein X stands for Br or I in the presence of magnesium in diethyl ether at the boil and treating the resultant tertiary alcohol with an acidic agent to provoke breaking of the isopropylidene ring and 3,4-cyclization; and to pharmaceutical compositions containing these derivatives.

The invention relates to furo-(3,4-c)-pyridine derivatives, to a processfor their preparation and to pharmaceutical compositions containingthem.

The invention provides1,3-dihydro-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine derivatives of thegeneral formula I (and their therapeutically acceptable addition salts):##STR2## wherein each of A₁ and A₂ independently represents a straightchain saturated or unsaturated hydrocarbon group having from 1 to 5carbon atoms, a heterocyclic group having up to 6 ring atoms, acarbomonocyclic group, a phenylalkyl group or a phenylalkenyl group,each of the groups represented by A₁ and A₂ being unsubstituted or beingsubstituted by one or more chlorine or fluorine atoms, trifluoromethylgroups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groupshaving from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5carbon atoms, dialkylamino groups in which each alkyl group has from 1to 5 carbon atoms, dialkylaminoalkoxy groups in which each of the twoalkyl groups and the alkoxy group has from 1 to 5 carbon atoms or α- orβalkoxy-N-pyrrolidinyl groups in which the alkoxy group has from 1 to 5carbon atoms.

The compounds according to the invention are of interest for theirtherapeutical activity, principally in the fields of diuresis, thelowering of blood pressure and kidney protection, and as anti-histaminicagents.

The invention further provides a process for the preparation of1,3-dihydro-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine derivatives of thegeneral formula I as above defined, the process comprising (i) oxidizingthe secondary alcoholα⁴,3-o-isopropylidene-1-methyl-5-(1-hydroxy-1-A₁)-methyl pyridine of theformula: ##STR3## by any usual technique, such as manganese dioxide, forinstance, which leads to a ketone, (ii) reacting the resultant ketonewith a compound of the general formula XA₂ wherein X stands for Br or Iand A₂ has the meaning given above, in the presence of magnesium indiethyl ether at the boil and (iii) treating the resultant tertiaryalcohol with an acidic agent to provoke breaking of the isopropylidenering and 3,4 cyclisation. The starting secondary alcohol is obtained asdescribed in our previous U.S. Pat. No. 4,383,998.

The process according to the invention is illustrated by the followingreaction scheme: ##STR4##

The invention also provides pharmaceutical compositions comprising afuro-(3,4-c)-pyridine derivative of the general formula I as hereindefined in admixture with a pharmaceutically acceptable diluent orcarrier.

The invention is illustrated by the following examples.

EXAMPLE 1 1,3-dihydro-3,3,6-trimethyl-7-hydroxy-furo-(3,4-c)-pyridine

Into a 3-liter reactor fitted with stirring, warming and cooling means,previously submitted to a nitrogen circulation, were poured 3.47 g(0.143 mol) of magnesium. Slowly, under stirring, there was then added20.3 g (0.143 mol) of methyl iodide dissolved in 400 ml of distilleddiethyl ether. The mixture was refluxed for 2 to 3 hours, then cooled to10°-15° C. and 22.8 g (0.11 mol of α⁴, 3-o-isopropylidene pyridoxaldissolved in 600 ml of distilled diethyl ether were slowly added. Themixture was stirred for 12 hours at room temperature, and then thediethyl ether was evaporated off under reduced pressure (end ofpreparation of starting secondary alcohol). 450 ml of dry methylenedichloride with 30.5 g (0.142 mol) of pyridinium chlorochromate and 2.35g (0.0285 mol) of pure and dry sodium acetate were poured all at onceinto the reactor and the mixture was stirred for 2 hours at roomtemperature, and then for some minutes, after addition of 200 ml of drydiethyl ether. After elimination of insoluble matter, the organic phasewas filtered and evaporated to dryness, leading to an oily product (endof step (ii)). This product was dissolved in 400 ml of diethyl ether andtreated under stirring for 12 hours at room temperature with a mixtureobtained by refluxing for 2 hours 400 ml of diethyl ether, 20 g (0.14mol) of methyl iodide and 3.45 g (0.14 mol) of magnesium. The diethylether was evaporated off under reduced pressure; after cooling, therewere added 0.5 l of chloroform and, dropwise, under stirring, 150 ml of2N hydrochloric acid. Stirring was maintained for 2 hours, the mixturewas decanted, the precipitate washed with water, dried on anhydroussodium sulphate, redissolved in diethyl ether, recrystallized, washedand dried (end of step (iii)). The compound thus obtained was thentreated with 100 ml of concentrated hydrochloric acid at roomtemperature, under stirring for 12 hours. The precipitate obtained wastreated twice by ethanol and recrystallized from acetone. Yield 15.9 g(67%) of a pale yellow product melting at 247° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₁₀ H₁₃NO₂ HCl. The product exhibited good solubility in water at roomtemperature.

EXAMPLE 21,3-dihydro-3-(n-pentyl)-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by n-pentyl bromide at step (iii). Yield: 72% of a productmelting at 222° C. (Tottoli), elemental analysis of which showed goodcorrespondence with the formula C₁₄ H₂₁ NO₂.HCl. The compound exhibitedvery good solubility in water at room temperature.

EXAMPLE 31,3-dihydro-3-phenyl-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by phenyl bromide in step (i). Yield: 69% of a cream-whiteproduct melting at 245° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₅ H₁₅ NO₂. The compound wasinsoluble in water at room temperature.

EXAMPLE 41,3-dihydro-3-(p-chlorophenyl)-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1, but usingp-chlorophenyl bromide instead of methyl iodide in step (i). Yield: 63%of a white crystalline powder melting at 228° C. (Tottoli), elementalanalysis of which showed good correspondence with the fomula C₁₅ H₁₄ClNO₂.HCl. The compound was insoluble in water at room temperature.

EXAMPLE 51,3-dihydro-3-(p-fluorophenyl)-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

The compound was obtained as described in example 1, but usingp-fluorophenyl bromide instead of methyl iodide in step (i). Yield: 71%of a white crystalline powder melting at 238° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₁₅ H₁₄FNO₂. The compound was insoluble in water at room temperature, butsoluble in 0.1N HCl.

EXAMPLE 61,3-dihydro-3-(α-thienyl)-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 2, but usingα-thienyl chloride instead of n-pentyl bromide. Yield 74% of a beigeproduct melting at 198° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₃ H₁₃ NO₂ S.HCl. The compound wassoluble in water.

EXAMPLE 71,3-dihydro-3-[2-(3,4,5-trimethoxyphenyl)-ethyl]-3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1, but replacing themethyl iodide by 1-chloro-2-(3,4,5-trimethoxyphenyl)ethane, in step (i).Yield: 83% of a white product melting at 219° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₂₀ H₂₅NO₅ HCl. The compound was soluble in water at room temperature.

EXAMPLE 81,3-dihydro-3-ethyl-3-(n-propyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1, but replacing themethyl iodide by n-propyl bromide in step (i) and by ethyl iodide instep (iii). Yield: 71% of a white crystalline product melting at 212° C.(Tottoli), elemental analysis of which showed good correspondence withthe formula C₁₃ H₁₉ NO₂.HCl. The compound was insoluble in water at roomtemperature.

EXAMPLE 91,3-dihydro-3-ethyl-3-(n-butyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 8, but replacing then-propylbromide by n-butyl bromide. Yield: 67% of a white crystallineproduct melting at 238° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₄ H₂₁ NO₂.HCl. The compound wasinsoluble in water at room temperature.

EXAMPLE 101,3-dihydro-3-ethyl-3-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was prepared as described in example 8, but replacing then-propyl bromide by phenyl bromide. Yield: 66% of a white crystallineproduct melting at 234° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₆ H₁₇ NO₂. The compound wasinsoluble in water at room temperature.

EXAMPLE 111,3-dihydro-3-ethyl-3-(p-chlorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 8, but replacing then-propyl bromide by p-chlorophenyl bromide. Yield: 77% of a cream-whiteproduct melting at 215° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₆ H₁₆ ClNO₂. The compound wasinsoluble in water at room temperature.

EXAMPLE 12 1,3-dihydro-3-ethyl-3-m-trifluoromethylphenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was prepared as described in example 8, but replacing then-propyl bromide by m-trifluoromethyl phenyl bromide. Yield: 69% of awhite crystalline product melting at 207°-208° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₁₆ H₁₆ F₃NO₂. The compound was insoluble in water at room temperature, butsoluble in 0.1N HCl.

EXAMPLE 131,3-dihydro-3-ethyl-3-(α-furyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 8, but replacing then-propyl bromide by α-furyl bromide. Yield: 73% of a pink productmelting at 192° C. (Tottoli) with decomposition, elemental analysis ofwhich showed good correspondence with the formula C₁₄ H₁₅ NO₃.HCl. Thecompound was insoluble in water at room temperature.

EXAMPLE 141,3-dihydro-3-vinyl-3-(p-methylthio-phenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by p-methylthio-phenyl bromide in step (i) and by vinylbromide in step (iii). Yield: 63% of a cream white crystalline productmelting at 200° C. (Tottoli), elemental analysis of which showed goodcorrespondence with the formula C₁₇ H₁₇ NO₂ S.HCl. The compound wasinsoluble in water at room temperature but soluble indimethylsulphoxide.

EXAMPLE 151,3-dihydro-3-propyl-3-p-chlorophenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by p-chlorophenyl bromide in step (i) and by propyl iodidein step (iii). Yield: 61% of a white crystalline product melting withdecomposition at 188°-190° C. (Tottoli), elemental analysis of whichshowed good correspondence with the formula C₁₇ H₁₈ ClNO₂. The compoundwas insoluble in water at room temperature but soluble in 0.1N HCl.

EXAMPLE 161,3-dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was prepared as described in example 15 but replacing thepropyl iodide by dimethylamino-propyl bromide. Yield: 56% of a whitecrystalline product melting at 212° C. (Tottoli), elemental analysis ofwhich showed good correspondence with the formula C₁₉ H₂₃ N₂ O₂ Cl. TheThe compound was insoluble in water at room temperature but soluble indimethylsulphoxide.

EXAMPLE 171,3-dihydro-3,3-diphenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by phenyl bromide in both steps (i) and (iii). Yield: 66%of a white crystalline powder melting at 260° C. (Tottoli) withdecomposition, elemental analysis of which showed good corresondencewith the formula C₂₀ H₁₇ NO₂.HCl. The compound was insoluble in water atroom temperature.

EXAMPLE 181,3-dihydro-3-phenyl-3-(p-toluyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 17 but replacing, instep (i), the phenyl bromide by P-toluyl bromide. Yield: 73% of a whitecrystalline product melting at 253° C. (Tottoli) with decomposition,elemental analysis of which showed good correspondence with the formulaC₂₁ H₁₉ NO₂.HCl. The compound was insoluble in water at roomtemperature.

EXAMPLE 191,3-dihydro-3-phenyl-3-(p-fluorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was prepared as described in example 17 using, in step(i), p-fluorophenyl bromide instead of phenyl bromide. Yield: 74% of awhite crystalline product melting at 259° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₂₀ H₁₆FNO₂.HCl. The compound was insoluble in water at room temperature.

EXAMPLE 201,3-dihydro-3-(p-trifluoromethylphenyl)-3-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 17 but replacing thephenyl bromide by p-trifluoromethylphenyl bromide in step (i). Yield:71% of a white crystalline product melting at 248° C. withdecomposition, elemental analysis of which showed good correspondencewith the formula C₂₁ H₁₆ F₃ NO₂.HCl. The compound was insoluble in waterat room temperature.

EXAMPLE 211,3-dihydro-3-(p-ethoxyphenyl)-3-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 17 but replacing thephenyl bromide by p-ethoxyphenyl bromide in step (i). Yield: 58% of awhite product melting at 230° C. (Tottoli), elemental analysis of whichshowed good correspondence with the formula C₂₂ H₂₁ NO₃.HCl. Thecompound was insoluble in water at room temperature.

EXAMPLE 221,3-dihydro-3-(p-diethylaminomethoxyphenyl)-3-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 16 but replacing, instep (iii), the phenyl bromide by p-diethylaminomethoxyphenyl bromide.Yield: 56% of a beige powder melting at 202° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₂₅ H₂₈ N₂O₃. The compound was insoluble in water at room temperature.

EXAMPLE 231,3-dihydro-3-{p-[N-(α-methoxypyrrolidinyl)]-phenyl}-3-phenyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 17 but replacing, instep (iii), the phenyl bromide by p-[N-(α-methoxypyrrolidinyl)]-phenylbromide. Yield: 73% of a white crystalline product melting at 189° C.(Tottoli), elemental analysis of which showed good correspondence withthe formula C₂₅ H₂₆ N₂ O₃.HCl. The compound was insoluble in water atroom temperature.

EXAMPLE 241,3-dihydro-3,3-di-(p-fluorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by p-fluorophenyl bromide in steps (i) and (iii). Yield:71% of a white crystalline product melting at 236°-239° C. (Tottoli),elemental analysis of which showed good correspondence with the formulaC₂₀ H₁₅ F₂ NO₂. The compound was insoluble in water at room temperaturebut soluble in dimethylsulphoxide.

EXAMPLE 251,3-dihydro-3-(α-furyl)-3-(p-methylthio-phenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 13 but replacing theethyl iodide, in step (iii), by p-thiomethylphenyl bromide. Yield 52% ofa beige powder melting at 176° C. (Tottoli), elemental analysis of whichshowed good correspondence with the formula C₁₉ H₁₇ NO₃ S.HCl. Thecompound was slightly soluble in water at room temperature.

EXAMPLE 261,3-dihydro-3,3-di(α-furyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 13 but replacing theethyl iodide, in step (iii), by α-furyl bromide. Yield 56% of a beigepowder melting at 184° C. (Tottoli), elemental analysis of which showedgood correspondence with the formula C₁₆ H₁₃ NO₄.HCl. The compound wasslightly soluble in water at room temperature.

EXAMPLE 271,3-dihydro-3-cyclohexyl-3-(2,3-dichlorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 but replacing themethyl iodide by 2,3-dichlorophenyl bromide in step (i) and bycyclohexyl bromide in step (iii). Yield: 76% of a white crystallineproduct melting with decomposition at 195°-197° C. (Tottoli), elementalanalysis of which showed good correspondence with the formula C₂₀ H₂₁Cl₂ NO₂. The compound was insoluble in water at room temperature butsoluble in 0.1N HCl.

EXAMPLE 281,3-dihydro-3-cyclohexyl-3-(p-chlorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 27 but replacing2,3-dichlorophenyl bromide as p-chlorophenyl bromide in step (i). Yield:79% of a white crystalline product melting at 205°-208° C. (Tottoli),elemental analysis of which showed good correspondence with the formulaC₂₀ H₂₂ ClNO₂. The compound was insoluble in water at room temperaturebut soluble in 0.1N HCl.

EXAMPLE 291,3-dihydro-3-cyclohexyl-3-(p-fluorophenyl)-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 28 but replacingp-chlorophenyl bromide by p-fluorophenyl bromide in step (i). Yield: 83%of a white crystalline product melting with decomposition at 208°-210°C. (Tottoli), elemental analysis of which showed good correspondencewith the formula C₂₀ H₂₂ FNO₂. The compound was insoluble in water atroom temperature but soluble in 0.1N HCl.

EXAMPLE 301,3-dihydro-3,3-dicyclohexyl-6-methyl-7-hydroxy-furo-(3,4-c)-pyridine

This compound was obtained as described in example 1 by using cyclohexylbromide in both steps. Yield: 69% of a white crystalline product meltingwith decomposition at 187°-190° C. (Tottoli), elemental analysis ofwhich showed good correspondence with the formula C₂₀ H₂₉ NO₂. Thecompound was insoluble in water at room temperature but soluble in 0.1NHCl.

TOXICITY

The toxicity of the compounds according to the invention has beendetermined on rats and mice, by oral route. No LD 50 could be found forno death was noticed at the dose of 5 g/Kg for rats and of 2 g/Kg formice.

A sub-acute toxicity study was undertaken on rats and dogs at the dosesof 10, 60 and 360 mg/Kg for six weeks by oral route: neither death wasnoticed nor any variation of the measurable factors.

PHARMACOLOGY

The interest of the compounds of the invention has been evidenced byvarious pharmacologic tests.

(1) Study of the urinary elimination in the rat

This study has been conducted on Wistar male rats weighing 250-260 g.

Sixteen batches of each eight animals were used: one for control, onetreated by tienilic acid as reference compound and fourteen batches bythe compounds according to the invention, all animals of these fifteenbatches at the same dose of 50 mg/kg/day.

The animals were treated for three days and placed in a metabolic cagefitted for the collection of urines; neither food nor drink was givenduring the treatment in order to avoid any contamination. The collectedvolumes of urine are measured after six hours and twenty four hours.After six hours, each animal receives 25 ml/kg of physiologic serum. Onthe fourth day, the animal receives a last treatment and blood is takenoff at the retro orbital sinus under slight anaesthesia by diethylether. The results are reported in the table 1.

(2) Action on blood pressure

This study was conducted on rats suffering from induced high bloodpressure, by the method of GOLDBLATT in comparison with Indapamine. Thismethod is no longer described, for it is well known and the study shows,at the same therapeutic doses, that the compounds of the invention have,on this test, the same action for the lowering of blood pressure on therats.

(3) Action on an experimental hyper lipemia on rabbit

This study has been conducted according to the method of C. B. AMMERMANand Coll.; Am. J. PHYS. (1961) 200, 75-79.

In this method, the suppression of drink for five days, induces in therabbit a higher hepatic bio-synthesis of cholesterol. Blood is taken offafter the sixth day in the abdominal aorta for the dosage of totallipids, triglycerids, total cholesterol, HDL cholesterol (enzymaticmethod after electrophoresis on cellulose acetate).

The livers are taken off and weighted. In all the cases theadministration was done directly in the oesophagus from the third to thefifth days. This experimentation has been conducted simultaneously on 15batches of each six animals, two control batches (normal control andcontrol without food), one reference batch (animal without food buttreated by tienilic acid) and the last twelve batches by twelve of thecompounds of the invention. These thirteen last batches receive 50mg/kg/day. The results are reported in table 2 wherein the letters A toF represent:

A: Weight of livers in g,

B: Total lipids in g/l,

C: Triglycerids in g/l,

D: Total cholesterol in g/l,

E: HDL cholesterol in g/l (two columns),

F: LDL cholesterol in g/l.

                  TABLE 1                                                         ______________________________________                                        Administration                                                                per os        Volumes (ml)                                                    of 50 mg/kg/day                                                                             0-6 h      6-24 h  0-24 h                                       ______________________________________                                        Control       5.7        14.1    19.8                                         Tienilic      8.0        8.9     16.7                                         acid                                                                          EX. 1         10.2       10.6    20.8                                         EX. 3         10.2       10.6    20.6                                         EX. 4         10.4       10.9    20.7                                         EX. 6         10.0       10.8    20.5                                         EX. 8         10.1       10.7    20.5                                         EX. 11        10.3       11.0    20.9                                         EX. 12        10.1       10.8    20.3                                         EX. 15        8.8        10.0    20.1                                         EX. 17        10.1       10.8    21.0                                         EX. 20        10.5       11.4    21.3                                         EX. 21        10.2       10.9    20.8                                         EX. 24        10.1       10.6    20.2                                         EX. 28        9.8        10.9    20.4                                         EX. 30        10.5       11.2    21.1                                         ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                             Cholesterol of                                                                            Total                                                             the         choles-                                               Plasmatic values                                                                          lipoproteins                                                                              terol                                        A          B      C       D    E     F     E                                  ______________________________________                                        Control                                                                              3.52    5.18   1.69  0.83 0.18  0.29  4.73                             Control                                                                              2.52    11.10  1.23  2.66 0.41  2.12  6.81                             without                                                                       food                                                                          Tienilic                                                                             2.80    12.28  1.97  2.48 0.23  1.77  15.72                            acid                                                                          EX. 1  2.63    11.05  1.48  2.51 0.31  1.70  8.01                             EX. 3  2.79    11.67  1.53  2.47 0.30  1.62  7.93                             EX. 6  2.72    11.44  1.57  2.50 0.24  1.65  8.17                             EX. 8  2.72    12.04  1.47  2.48 0.27  1.67  8.31                             EX. 11 2.65    11.56  1.61  2.50 0.28  1.67  7.79                             EX. 12 2.66    12.10  1.62  2.46 0.29  1.63  8.16                             EX. 15 2.77    11.86  1.44  2.49 0.25  1.66  8.19                             EX. 17 2.70    11.93  1.49  2.47 0.27  1.64  8.24                             EX. 20 2.69    11.79  1.44  2.51 0.26  1.64  8.12                             EX. 24 2.78    11.97  1.48  2.46 0.27  1.70  7.85                             EX. 28 2.62    11.46  1.46  2.45 0.23  1.64  8.22                             EX. 30 2.65    11.88  1.50  2.53 0.29  1.67  8.22                             ______________________________________                                    

In conclusion of the various experimentations it can be noticed that thecompounds of the invention have a regular diuretic action slightlybetter than the known diuretics of the same chimical family (thiazidic).In human therapy, they have also an action on the lowering of bloodpressure which is rather common in diuretics but limited to the patientspresenting an hypertension. An other important fact is a significativelowering of the lipid rates in blood: this is a highly favorable action,for the patients treated by diuretics are generally suffering also fromarteriosclerosis or other circulary insufficiencies wherein the loweringof the lipid rates is highly desired. For this reason, the compounds ofthe invention may be considered as diuretics offering a betterprotection of the patient.

CLINICAL EXPERIMENTATION

A clinical experimentation has been conducted on 127 patients withcompounds of examples 3, 4 and 5. Each patient was treated as follows:on days 1, 3, 5 and 7, administration (double blind route) of a singledose of 100 mg or 200 mg or 400 mg of the selected compound or anequivalent presentation of placebo at 10.00 a.m. after a completeurination. Urins were collected for the following 24 hours fordetermination of the diuresis. No treatment was given on days 2, 4 and6.

The diuresis was increased by 130 to 164% at the dose of 100 mg, by 192to 248% at the dose of 200 mg and 288 to 371% at the dose of 400 mg(percentages given by reference to the action of placebo) with a bettertolerance than with the compounds of U.S. Pat. No. 4,383,998 previouslyreferred to.

PRESENTATION

The preferred mode of administration includes tablets and gelatinecapsules; for tablets the dosage units comprise 50 or 100 mg of activeingredient together with an appropriate carrier, such as, for instance,starch.

POSOLOGY

In human therapy it is generally advisable to administer 100 to 400 mgper diem for at least one week and, more generally, two or three weeks.

I claim:
 1. A 1,3-dihydro-6-methyl-7-hydroxy-furo-(3,4-c)-pyridinederivative of the formula I ##STR5## wherein each of A₁ and A₂independently represents a straight chain saturated or unsaturatedhydrocarbon group having from 2 to 5 carbon atoms, a thienyl or furylgroup, a carbomonocyclic group, a phenylalkyl group or a phenylalkenylgroup, each of the groups represented by A₁ and A₂ being unsubstitutedor being substituted by one or more chlorine or fluorine atoms,trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms,alkoxy groups having from 1 to 5 carbon atoms, alkylthio groups havingfrom 1 to 5 carbon atoms, dialkylamino groups in which each alkyl grouphas from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in which each ofthe two alkyl groups and the alkoxy group has from 1 to 5 carbon atomsor α- or β-alkoxy-N-pyrrolidinyl groups in which the alkoxy group hasfrom 1 to 5 carbon atoms; and therapeutically acceptable addition saltsthereof.
 2. A diuretic, hypotensive and hypolipidemic compositioncomprising an amount sufficient to be effective as a diuretic,hypotensive or hypolipidemic agent of a furo-(3,4-c)-pyridine derivativeas defined in claim 1, in admixture with a pharmaceutically acceptablediluent or carrier.